Leukotriene-B4 derivatives, in particular 7-methylcyclohexyl-LTB4 antagonists

Abstract

The invention relates to leukotriene B 4 derivatives of general formula (I) in which R 1 stands for CH 2 OH, CH 3 , CF 3 , COOR 4 , CONR 5 R 6 ; R 2 stands for H or an organic acid radical with 1-15 C atoms; R 3 stands for H; R 4 is hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -cycloalkyl, a C 6 -C 10 -aryl radical optionally substituted by 1-3 halogen, phenyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy, or CH 2 —CO—(C 6 -C 10 ) aryl, or a 5-6 link ring with at least 1 heteroatom; A is a trans-, trans-CH═CH—CH═CH, a —CH 2 CH 2 —CH═CH— or a tetramethylene group; B is a C 1 -C 10 linear or branched-chain aklylene group or the group (a) or (b); D is a direct bonding, oxygen, sulphur, —C≡C—, —CH═CR 7 , or a direct bonding with B. The invention also relates to salts thereof, having physiologically compatible bases and their cyclodextrin clathrates. The inventive substances can be used as pharmaceutical preparations

What is claimed is:  
     
       1. A leukotriene-B 4  derivative of formula I                    
       wherein 
       R 1  is CH 2 OH, CH 3 , CF 3 , COOR 4 , or CONR 5 R 6 ,  
       R 2  is H or an organic acid radical with 1-15 C atoms,  
       R 3  is H; C 1 -C 4  alkyl optionally substituted by halogen atoms or phenyl; C 3 -C 10  cycloalkyl optionally substituted in one or more places by C 1-4  alkyl or halogen atoms; C 6 -C 10  aryl optionally substituted in one or more places by halogen, phenyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy; or a 5- to 6-membered aromatic heterocyclic ring with at least 1 heteroatom,  
       R 4  is hydrogen; C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, or C 6 -C 10  aryl in each case optionally substituted by 1-3 halogen, phenyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy; CH 2 —CO—(C 6 -C 10 ) aryl; or a 5- to 6-membered ring with at least 1 heteroatom,  
       A is trans, trans-CH═CH—CH═CH, —CH 2 CH 2 —CH═CH— or tetramethylene,  
       B is C 1 -C 10  straight-chain or branched-chain alkylene, which is optionally substituted by fluorine, or is                    
       D is a direct bond, oxygen, sulfur, —C≡C—, —CH═CR 7  or together with B can also be a direct bond;  
       R 5  and R 6  are the same or different, and are each H or C 1 -C 4  alkyl optionally substituted by hydroxy groups, or R 6  is H and R 5  is C 1 -C 15  alkanoyl or R 8 SO 2 ,  
       R 7  is H, C 1 -C 5  alkyl, chlorine, or bromine,  
       R 8  is H; C 1 -C 14  alkyl optionally substituted by halogen atoms or phenyl; C 3 -C 10  cycloalkyl optionally substituted in one or more places by C 1-4  alkyl or halogen atoms; C 6 -C 10  aryl optionally substituted in one or more places by halogen, phenyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy; or a 5- to 6-membered aromatic heterocyclic ring with at least 1 heteroatom,  
       m is 1-3,  
       n is 2-5,  
       o is 0-5,  
       p is 0-5,  
       X is a direct bond, oxygen, or sulfur, and  
       Y is C 1 -C 8  alkyl optionally substituted in one or more places, or C 3 -C 10  cycloalkyl optionally substituted by aryl,  
       and, if R 4  is hydrogen, salts thereof with physiologically compatible bases and cyclodextrin clathrates thereof. 
     
     
       2. A pharmaceutical composition comprising a leukotriene-B 4  derivative according to  claim 1 , and an additive for forming a solution, cream or ointment. 
     
     
       3. A process for production of leukotriene-B 4  derivatives according to  claim 1 , comprising reacting a ketone of formula II                    
       optionally under protection of free hydroxy groups in R 2 , with an olefination reagent of formula III, 
       
         
           E—CH 2 —(CH 2 ) o —X—(CH 2 ) p —R 1   (III)  
         
       
       wherein E is                    
       in the presence of a base, and 
       optionally separating isomers,  
       optionally releasing protected hydroxy groups,  
       optionally etherifying a free hydroxy group  
       optionally oxidizing the 1-hydroxy group to carboxylic acid and/or is reduced,  
       optionally esterifying a carboxyl group  
       optionally converting a free carboxyl group into an amide, or  
       optionally a carboxyl group is converted into a salt with a physiologically compatible base.  
     
     
       4. A compound according to  claim 1 , wherein Y is C 1 -C 8  alkyl or C 3 -C 10  cycloalkyl. 
     
     
       5. A compound according to  claim 4 , wherein the group OR 2  is in the α-position. 
     
     
       6. A compound according to  claim 4 , wherein the group OR 2  is in the β-position. 
     
     
       7. A compound according to  claim 4 , wherein R 4  is H; 
       straight-chain or branched-chain alkyl having 1-10 C atoms;  
       cycloalkyl having 3-10 C atoms which is optionally substituted by alkyl having 1-4 C atoms;  
       aryl having 6-10 C atoms which is optionally substituted by 1-3 halogen atoms, phenyl, 1-3 alkyl groups having 1-4 C atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy having 1-4 C atoms; or  
       a 5- or 6-membered aromatic heterocycle selected from 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, 3-furyl, 3-thienyl, and 2-tetrazolyl.  
     
     
       8. A compound according to  claim 4 , wherein R 2  is H or an acid radical selected from the following acids: 
       formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, ethanic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid, benzoic acid and benzoic acid substituted with F, Cl, Br, trifluoromethyl, hydroxy, C 1  alkoxy or carboxy groups.  
     
     
       9. A compound according to  claim 4 , wherein R 3  is a straight-chain or branched-chain, saturated or unsaturated alkyl group having 1-14 C atoms which is optionally substituted by phenyl or halogen atoms. 
     
     
       10. A compound according to  claim 4 , wherein R 3  is a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, and fluorocyclohexyl. 
     
     
       11. A compound according to  claim 4 , wherein R 3  is phenyl, 1-naphthyl or 2-naphthyl which is optionally substituted by 1-3 halogen atoms, phenyl, 1-3 alkyl groups having 1-4 C atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C 1 -C 4  alkoxy, or hydroxy. 
     
     
       12. A compound according to  claim 4 , wherein R 3  is a 5- and/or 6-membered heterocyclo selected from 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, and 3-thienyl. 
     
     
       13. A compound according to  claim 4 , wherein group B is selected from methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1,2-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl-trimethylene, 1-methylene-ethylene, 1-methylene-tetramethylene, or is a group of formula                    
       in which n is 3-5. 
     
     
       14. A compound according to  claim 1 , wherein 
       R 1  is CH 2 OH, CONR 5 R 6 , or COOR 4 ,  
       R 4  is a hydrogen, alkyl with 1-10 C atoms, cycloalkyl with 5-6 C atoms, phenyl optionally substituted by 1-2 chlorine, bromine, phenyl, C 1-4  alkyl, C 1-4  alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy,  
       X is an oxygen atom,  
       Y is methyl,  
       p is 1-3,  
       o s 1-3,  
       m is 1-3,  
       A is trans-CH═CH—CH═CH— or tetramethylene;  
       B is a straight-chain or branched-chain, saturated or unsaturated, alkylene group with up to 10 C atoms, which is optionally substituted by fluorine, or is                    
       n is 2-5,  
       D is a direct bond, oxygen, sulfur, —C≡C— or —CH═CR 7 ,  
       R 7  is hydrogen, C 1-5  alkyl, chlorine or bromine;  
       B and D together are, alternatively, a direct bond;  
       R 2  is hydrogen or an organic acid radical with 1-15 C atoms;  
       R 3  is hydrogen, C 1 -C 10  alkyl, cycloalkyl with 5-6 C atoms, or phenyl optionally substituted by 1-2 chlorine, bromine, phenyl, C 1-4  alkyl, C 1-4  alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy,  
       or if R 4  is hydrogen, a salt thereof with a physiologically compatible base, or a cyclodextrin clathrate thereof. 
     
     
       15. A compound according to  claim 1 , wherein 
       R 1  is CH 2 OH, CONR 5 R 6 , or COOR 4    
       R 4  is hydrogen, or alkyl with 1-4 C atoms;  
       R 2  is hydrogen or an organic acid radical with 1-6 C atoms;  
       R 3  is hydrogen or C 1-10  alkyl;  
       A is trans, trans-CH═CH—CH═CH— or tetramethylene;  
       B is a straight-chain or branched-chain alkylene group with up to 5 C atoms, or is                    
       n is 3 or 4;  
       D is a direct bond, —C≡C or a —CH═CR 7 ,  
       R 7  is hydrogen or C 1-5  alkyl;  
       X is an oxygen atom,  
       Y is methyl,  
       p is 1,  
       o is 1,  
       m is 1, 2;  
       B and D are, alternatively, a direct bond;  
       or, if R 4  is hydrogen, a salt thereof with a physiologically compatible base, or a cyclodextrin chlathrate thereof. 
     
     
       16. A leukotriene-B 4  derivative of formula I                    
       wherein 
       R 1  is CH 2 OH, CH 3 , CF 3 , COOR 4 , or CONR 5 R 6 ;  
       R 2  is H or an organic acid radical selected from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, ethanic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acid substituted with F, Cl, Br, trifluoromethyl, hydroxy, C 1-4  alkoxy or carboxy groups; nicotrinic acid, isonicotinic acid, furan-2-carboxylic acid, and cyclopentylpropionic acid,  
       R 3  is H; methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m-chlorobenzyl, p-chlorobenzyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, fluorocyclohexyl; phenyl, 1-naphthyl or 2-naphthyl which is optionally substituted by 1-3 halogen atoms, phenyl, 1-3 alkyl groups having 1-4 C atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C 1 -C 4  alkoxy, or hydroxy; 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, or 3-thienyl;  
       R 4  is H; straight-chain or branched-chain alkyl having 1-10 C atoms which is optionally substituted by halogen atoms, methoxy, ethoxy, aryl having 6-10 C atoms, aroyl having 6-10 C atoms, dialkylamino wherein the alkyl portions have 1-4 C atoms, or trialkylammonium wherein the alkyl portions have 1-4 C atoms; cycloalkyl having 3-10 C atoms which is optionally substituted by alkyl having 1-4 C atoms; aryl having 6-10 C atoms which is optionally substituted by 1-3 halogen atoms, phenyl, 1-3 alkyl groups having 1-4 C atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy having 1-4 C atoms; 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, 3-furyl, 3-thienyl, or 2-tetrazolyl;  
       A is trans, trans-CH═CH—CH═CH, —CH 2 CH 2 —CH═CH— or tetramethylene;  
       B is C 1 -C 10  straight-chain or branched-chain alkylene, which is optionally substituted by fluorine, or is                    
       D is a direct bond, oxygen, sulfur, —C≡C—, —CH═CR 7  or together with B can also be a direct bond;  
       R 5  and R 6  are the same or different, and are each H or C 1 -C 4  alkyl optionally substituted by hydroxy groups, or R 6  is H and R 5  is C 1 -C 15  alkanoyl or R 8 SO 2 ,  
       R 7  is H, C 1 -C 5  alkyl, chlorine, or bromine,  
       R 8  is H; methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m-chlorobenzyl, p-chlorobenzyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, fluorocyclohexyl; phenyl, 1-naphthyl or 2-naphthyl which is optionally substituted by 1-3 halogen atoms, phenyl, 1-3 alkyl groups having 1-4 C atoms, chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C 1 -C 4  alkoxy, or hydroxy; 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, or 3-thienyl;  
       m is 1-3,  
       n is 2-5,  
       o is 0-5,  
       p is 0-5,  
       X is a direct bond, oxygen, or sulfur, and  
       Y is C 1 -C 8  alkyl or C 3 -C 10  cycloalkyl optionally substituted by aryl,  
       and, if R 4  is hydrogen, salts thereof with physiologically compatible bases and cyclodextrin clathrates thereof.